One type of the mechanisms of cell death is so called as "Apoptosis", and has been described, inter alia, by KERR J. F. R. et al., J. Cancer, 265, 239 (1972). It is understood that apoptosis is a highly selective form of cellular suicide which is characterized by easily observable morphological and biochemical phenomena. Condensation of chromatin associated or not with exonucleases activation, formation of apoptotic bodies and fragmentation of deoxyribonucleic acid (DNA) to 180-200 base pairs DNA fragments thereby providing an easily recognizable profile by agarose gel electrophoresis are thus observed.
A wide variety of natural or synthetic anticancer drugs is currently available.
Alkylating agents such as cyclophosphamides, nitrosoureas such as 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), intercalating agents such as actinomycin D or adriamycin, purine or pyrimidine base analogues such as 6-thioguanine and 5-fluorouracil, inhibitors of de novo synthesis of purine bases such as methotrexate and tubulin polymerization inhibitors such as Taxol.RTM. may be cited inter alia as antineoplastic drugs.
One of the main disadvantages of the use of these substances is the lack of a selective apoptotic activity against tumour cells. Thus, the major problem for preparing such compounds is to design and prepare molecules which induce maximum apoptosis in tumour tissues while injuring healthy tissues as little as possible and in a reversible manner.
In order to overcome the lack of selectivity, the applicant has already proposed, particularly in Patent Application WO 96/20701, the use apoptosis-inducing compounds chosen from methional, malonaldehyde and any factor capable to promote an increase of the intracellular level of these compounds, or interfere with the metabolism of methional which is displayed in FIG. 1 (QUASH et al., Biochem. J. 305, 1017 (1995)).
Ester compounds of L-methionine and pyridoxal have been described in Patent Application WO 96/20701 as factors capable of increasing the intracellular level of methional. In effect, these compounds inhibit the conversion of 4-methylthio-2-oxobutanoic acid (MTOB) to methionine by the MTOB transaminase enzyme, thereby causing accumulation of MTOB which is a direct precursor of methional (See FIG. 1) (ROCH et al., Biochem. J. 313, 973 (1996)).
However, the selectivity of methional and malonaldehyde against tumour cells was again proved insufficient since these compounds inhibit the growth of both tumour cells and normal cells to the same extent.
The use of an aminothioester derivative, designated AMPALTE, as an inhibitor of the enzyme aldehyde dehydrogenase (ALDH), i.e., an enzyme involved in the conversion of methional to methylthiopropionic acid, thereby promoting accumulation of methional, has also been described by the applicant in Patent Application FR-9704283. This compound is a selective inhibitor of the growth of transformed cells which are resistant to apoptosis because of the overexpression of the anti-apoptotic gene bcl.sub.2.
Such a compound is therefore more specifically intended for pathological conditions characterized by overexpression of the bcl.sub.2 gene such as breast cancers, B-cell lymphomas, leukaemias, neuroblastomas, prostate adenocarcinomas, prolactinomas and other pituitary adenomas.
It was therefore desirable to develop a therapeutic strategy which is selective against tumour cells and to target a large number of cancer pathologies.
Following numerous studies on various methional derivatives, it has been observed that the derivatives comprising methional coupled by a thioester bond to thioctic acid had a highly selective apoptotic activity against transformed and tumour cells, as demonstrated by the experimental data presented in the application.
Such an activity makes the compounds of the invention useful in antitumour therapeutic treatment.